Rab32 promotes glioblastoma migration and invasion via regulation of ERK/Drp1-mediated mitochondrial fission

Abstract

Background and objective: The highly widespread and infiltrative nature of glioblastoma multiforme (GBM) makes complete surgical resection hard, causing high recurrence rate and poor patients’ prognosis. However, the mechanism underlying GBM migration and invasion is still unclear. In this study, we investigated the role of a Ras-related protein Rab32 on GBM and uncovered its underlying molecular and subcellular mechanisms that contributed to GBM aggressiveness. Method: The correlation of Rab32 expression with patient prognosis and tumor grade was investigated by public dataset analysis and clinical specimen validation. The effect of Rab32 on migration and invasion of GBM had been evaluated using wound healing assay, cell invasion assay, as well as protein analysis upon Rab32 manipulations. Mitochondrial dynamics of cells upon Rab32 alterations were detected by immunofluorescence staining and western blotting. Both the subcutaneous and intracranial xenograft tumor model were utilized to evaluate the effect of Rab32 on GBM in vivo. Results: The expression level of Rab32 is significantly elevated in the GBM, especially in the most malignant mesenchymal subtype, and is positively correlated with tumor pathological grade and poor prognosis. Knockdown of Rab32 attenuated the capability of GBM’s migration and invasion. It also suppressed the expression levels of invasion-related proteins (MMP2 and MMP9) as well as mesenchymal transition markers (N-cadherin, vimentin). Interestingly, Rab32 transported Drp1 to mitochondrial from the cytoplasm and modulated mitochondrial fission in an ERK1/2 signaling-dependent manner. Furthermore, silencing of Rab32 in vivo suppressed tumor malignancy via ERK/Drp1 axis. Conclusion: Rab32 regulates ERK1/2/Drp1-dependent mitochondrial fission and causes mesenchymal transition, promoting migration and invasion of GBM. It serves as a novel therapeutic target for GBM, especially for the most malignant mesenchymal subtype.

Exploring neuroadaptive cellular pathways in chronic morphine exposure: An in‐vitro analysis of cabergoline and Mdivi‐1 co‐treatment effects on the autophagy–apoptosis axis

“…This result suggests the possible existence of alternate signaling pathways where this cell line is a representative, offering intriguing avenues for further research, especially given the recent documentation of high DRP1 expression in cancers like NB and GBM 110,111 . Leveraging on previous research, we suggest that targeting DRP1‐dependent mitochondrial fission may hold promise in addressing cell death processes and potentially overcoming chemoresistance in GBM studies 66 …”

“…Additionally, neither acute nor chronic morphine treatment appears to influence DRP1 expression in nonneural GBM cell lines; however, previous studies suggest that the DRP1 pathway participates actively in facilitating migration and invasion of GBM cells, highlighting its role in proliferation and spread of GBM. 66 Strategies to decrease DRP1 expression could obstruct DNA repair mechanisms while heightening the radiosensitivity of GBM cells. 67 Nevertheless, there exists a noticeable gap in the research regarding this issue.…”

“…110,111 Leveraging on previous research, we suggest that targeting DRP1-dependent mitochondrial fission may hold promise in addressing cell death processes and potentially overcoming chemoresistance in GBM studies. 66 A critical evaluation of current research reveals conflicting viewpoints regarding the role of mitochondrial fission in mediating apoptotic or antiapoptotic effects. It is unequivocal that mitochondrial fission is instrumental in facilitating apoptosis.…”

LINC00606 promotes glioblastoma progression through sponge miR-486-3p and interaction with ATP11B

“…The strong proliferation and migration characteristics of glioma cells are the main reason for the low cure rate, postoperative recurrence, and poor prognosis [3]. ATP11B has been shown to be closely associated with tumor metastasis; however, its role in glioma has not yet been elucidated.…”

“…Owing to advancements in medical technology and clinical treatment guidelines, progress has been made in predicting regulatory molecules and optimizing treatment strategies for glioblastoma (GBM); however, prognosis remains poor, and the target genes for effective intervention in GBM progression need to be further explored [1][2][3][4]. There is an urgent need to uncover the potential molecular mechanisms involved in glioma progression with a view to improving therapeutics [5,6].…”